Yoon-Mi Lee1, Jun-Ha Choi1, Wan-Kwon Min1, Jong-Kwon Han2, Jae-Wook Oh3. 1. Department of Animal Biotechnology, College of Animal Bioscience and Technology, Konkuk University, Seoul 05029, Republic of Korea. 2. Department of Research and Development Center, Milae Resource ML Co. Ltd., Seoul 05836, Republic of Korea. 3. Department of Animal Biotechnology, College of Animal Bioscience and Technology, Konkuk University, Seoul 05029, Republic of Korea. Electronic address: ohjw@konkuk.ac.kr.
Abstract
AIMS: The aim of this study was to evaluate gamma-aminobutyric acid (GABA)- and piperine-induced erythropoietin (EPO) and EPO-receptor expression. MATERIALS AND METHODS: The effect of GABA and piperine on cell viability was examined using kidney epithelial cells. Expression levels of EPO and EPO-R mRNA and protein were evaluated in response to GABA and piperine treatments. GABA- and piperine-mediated activation of the mitogen-activated protein kinase (MAPK) signaling pathway was investigated. Additionally, EPO function was evaluated using conditioned media containing EPO. The GABA receptor type involved in this process was identified. KEY FINDINGS: Messenger RNA and protein expression levels of EPO and EPO-R significantly increased in response to treatment with GABA, piperine, or the combination of both, compared with control. GABA plus piperine synergistically enhanced EPO and EPO-R expression through p38 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways, but not through the extracellular signal-regulated kinase (ERK) MAPK pathway. SB203580 and SP600125 (p38 and JNK pathway inhibitors, respectively) attenuated GABA plus piperine-induced EPO and EPO-R expression. Treatment of macrophages with EPO-containing conditioned media induced mRNA expression of interleukin (IL)-10 and nuclear factor (NF)-κB due to the interaction between EPO and EPO-R. Interestingly, GABA-induced EPO and EPO-R expression was mediated through GABAA, not GABAB, receptor activation. SIGNIFICANCE: These findings demonstrate that GABA plus piperine-mediated p38 and JNK MAPK activation increases EPO and EPO-R expression, resulting in up-regulation of IL-10 and NF-κB.
AIMS: The aim of this study was to evaluate gamma-aminobutyric acid (GABA)- and piperine-induced erythropoietin (EPO) and EPO-receptor expression. MATERIALS AND METHODS: The effect of GABA and piperine on cell viability was examined using kidney epithelial cells. Expression levels of EPO and EPO-R mRNA and protein were evaluated in response to GABA and piperine treatments. GABA- and piperine-mediated activation of the mitogen-activated protein kinase (MAPK) signaling pathway was investigated. Additionally, EPO function was evaluated using conditioned media containing EPO. The GABA receptor type involved in this process was identified. KEY FINDINGS: Messenger RNA and protein expression levels of EPO and EPO-R significantly increased in response to treatment with GABA, piperine, or the combination of both, compared with control. GABA plus piperine synergistically enhanced EPO and EPO-R expression through p38 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways, but not through the extracellular signal-regulated kinase (ERK) MAPK pathway. SB203580 and SP600125 (p38 and JNK pathway inhibitors, respectively) attenuated GABA plus piperine-induced EPO and EPO-R expression. Treatment of macrophages with EPO-containing conditioned media induced mRNA expression of interleukin (IL)-10 and nuclear factor (NF)-κB due to the interaction between EPO and EPO-R. Interestingly, GABA-induced EPO and EPO-R expression was mediated through GABAA, not GABAB, receptor activation. SIGNIFICANCE: These findings demonstrate that GABA plus piperine-mediated p38 and JNKMAPK activation increases EPO and EPO-R expression, resulting in up-regulation of IL-10 and NF-κB.
Authors: Pengfei Sun; Nitin Kumar; Adrienne Tin; Jing Zhao; Michael R Brown; Zesen Lin; Min-Lee Yang; Qiwen Zheng; Jia Jia; Lawrence F Bielak; Bing Yu; Eric Boerwinkle; Kristina L Hunker; Josef Coresh; Y Eugene Chen; Yong Huo; Sharon L R Kardia; Rami Khoriaty; Xiang Zhou; Alanna C Morrison; Yan Zhang; Santhi K Ganesh Journal: Hypertension Date: 2021-09-07 Impact factor: 10.190